We propose to investigate why central visual pathways fail to regenerate after injury and how their repair can be enhanced. Our focus in this proposal is on understanding and overcoming CMS myelin inhibition of axon regeneration. Over the last grant period, we identified a novel myelin inhibitor, which is a myelin-specific lipid called sulfatide, that is strongly inhibitory to axon growth. In the first aim, we will test the hypothesis that sulfatide is a major myelin inhibitor of axon regeneration in vitro and in vivo, and further characterize the mechanism by which it inhibits axon growth. Second, we have been investigating why clearance of degenerating CNS myelin after CNS injury is so slow, when in contrast clearance of PNS myelin is relatively rapid. Degenerating myelin persists in the human CNS for years and thus may contribute long-lasting inhibitory cues that prevent axon regeneration. Over the last grant period we discovered that the rapid clearance of PNS myelin depends on the generation of auto- antibodies to degenerating myelin. This finding suggests the hypothesis that degenerating CNS myelin is not cleared robustly because of the blood-brain barrier and CNS immunoprivilege, and also suggests a novel mechanism of action for the ability of Nogo antibodies to promote CNS regeneration. In the second aim, we will further characterize how antibodies enhance myelin clearance in the PNS. In the third and final aim, we will investigate whether delivery of antibodies to degenerating CNS myelin will speed clearance of degenerating CNS myelin and whether this will promote CNS axon regeneration. If so, these experiments will provide strong evidence for the contribution of myelin inhibition to CNS regenerative failure and indicate that antibodies to degenerating CNS myelin may be a useful therapeutic strategy. In these experiments we will focus on the ability of mouse retinal ganglion cells to regenerate after optic nerve crush. Our ultimate goal is to understand why retinal ganglion cells fail to regenerate after axotomy and to develop new treatments to promote their regeneration after injury in ocular diseases including glaucoma, retinal ischemia, optic neuritis, and neuropathy.